A subject of the present invention is new derivatives of amidines which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates in particular to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS""s in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
Proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, angiogenesis, amyloidoses, inflammations of the gastro-intestinal system (ulcerative or non ulcerative colitis, Crohn""s disease), diarrhea.
Diseases affecting the pulmonary system or airways (asthma, sinusitis, rhinitis).
Cardio-vascular and cerebro-vascular disorders including for example, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemia and thromboses;
Disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid hemorrhaging, aging, senile dementia including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis; ocular neuropathies such as glaucoma but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, cognitive disorders, encephalopathies, and encephalopathies of viral or toxic origin;
Disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
Cataracts.
Organ transplants.
Autoimmune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, and multiple sclerosis.
Cancer.
Neurological diseases associated with intoxication (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
All the pathologies characterized by an excessive production or dysfunction of NO and/or ROS""s.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS""s (J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).
Moreover, in earlier patents, the inventors already described NO Synthase inhibitors and their use (Patents U.S. Pat. Nos. 5,081,148; 5,360,925), and more recently the combination of these inhibitors with products possessing antioxidant or antiradicular properties (Patent Application PCT WO 98/09653). In applications not yet published, they also described other derivatives of amidines or, more recently, derivatives of aminopyridines. These derivatives of amidines or aminopyridines have the characteristic of being both inhibitors of NO Synthases and inhibitors of ROS.
A subject of Application WO 95/05363 is compounds which are inhibitors of NO synthases of general formula (A1) 
in which
D represents phenyl, pyridinyl or an aromatic heterocycle with 5 members containing 1 to 4 heteroatoms chosen form O, N and S, these three groups being optionally substituted by one or more groups chosen from (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C1-C6)perfluoralkyl, or D represents (C1-C6)perfluoroalkyl;
R1 represents hydrogen, (C1-C6)alkyl or halogen;
R2 represents xe2x80x94X(CH2)nZCONR3R4, xe2x80x94X(CH2)nNHCO(CH2)sNR3R4, xe2x80x94X(CH2)PNR3R4, xe2x80x94X(CH2)nNHCOR5OR(CH2)qNHC(NH)R6,
R3 and R4 independently represent hydrogen, (C1-C6)alkyl, xe2x80x94(CH2)rA, xe2x80x94(CH2)mOA or xe2x80x94CH(CH3)(CH2)tA;
or the NR3R4 group represents 1-indanyl, piperonylamino, piperidynyl, morpholinyl, pyrrolidinyl, 1,2,3,4-tetrahydroisoquinolinyl or piperazinyl optionally substututed in position 4 by (C1-C6)alkyl;
R5 represents (C1-C6)alkyl, (C1-C6)perfluoroalkyl, xe2x80x94(CH2)rxe2x80x94A or xe2x80x94O(CH2)wA;
A represents phenyl, pyridinyl, pyrimidinyl or an aromatic heterocycle with 5 members containing 1 to 4 heteroatoms chosen form O, N and S, these 4 groups being optionally substituted by one or more groups chosen from (C1-C6)alkyl, halogen, nitro, cyano and trifluoromethyl;
R6 represents phenyl, pyridinyl or an aromatic heterocycle with 5 members containing 1 to 4 heteroatoms chosen form O, N and S, these three groups being optionally substituted by one or more groups chosen from (C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C1-C6)perfluoralkyl, or R6 represents (C1-C6)perfluoroalkyl;
n and r independently represent integers from 0 to 6;
p and w independently represent integers from 1 to 5;
m represents an integer from 2 to 5;
q and t independently represent integers from 0 to 5;
s represents an integer from 1 to 3;
X represents O or a bond;
Z represents O, NR7 or a bond;
R7 represents hydrogen or (C1-C6)alkyl;
it being understood that:
(a) D, when it contains a heteroatom, is not connected to the remainder of the compound of formula (A1) by the heteroatom;
(b) when R2 represents xe2x80x94X(CH2)nZCONR3R4 and neither X nor Z represents a bond then n represents an integer from 2 to 6;
(c) when R2 represents xe2x80x94X(CH2)nNHCO(CH2)sNR3R4 or a xe2x80x94X(CH2)nNHCOR5 and X represents O, then n represents an integer from 2 to 6;
(d) when R2 represents xe2x80x94X(CH2)pNR3R4 and X represents O, then p represents an integer from 2 to 5;
(e) when R2 represents xe2x80x94(CH2)qNHC(NH)R6, R1 represents hydrogen, D represents phenyl and R6 represents phenyl, then q does not represent 0;
(f) when R2 represents xe2x80x94(CH2)qNHC(NH)R6, R1 represents hydrogen, D and R6 represent 2-chlorophenyl, then q does not represent 0;
(g) when R2 represents xe2x80x94(CH2)qNHC(NH)R6, R1 represents hydrogen, D and R6 represent 3-pyridinyl, then q does not represent 0; and
(h) when R2 represents xe2x80x94(CH2)qNHC(NH)R6, R1 represents hydrogen, D and R6 represent 4-pyridinyl, then q does not represent 0.
A subject of the Patent Application PCT WO 98/42696 is compounds which are inhibitors of NO synthases and ROS traps of general formula (A2) 
in which
A represents one of the 
xe2x80x83radicals in which R1 and R2 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R3 represents a hydrogen atom, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COR4 radical,
R4 represents a linear or branched alkyl radical having 1 to 6 carbon atoms,
and R5 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
X represents xe2x80x94Z1, xe2x80x94Z1xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94COxe2x80x94, xe2x80x94Z1xe2x80x94NR3xe2x80x94COxe2x95x90, xe2x80x94Z1xe2x80x94NR3xe2x80x94CSxe2x80x94, xe2x80x94Z1NR3xe2x80x94SO2xe2x80x94 or a single bond;
Y represents a radical chosen from the xe2x80x94Z2xe2x80x94Q, piperazine, homopiperazine, 2-methylpiperazine, 2,5 dimethylpiperazine, 4-aminopiperidine, xe2x80x94NR3xe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94COxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94NR3xe2x80x94NHxe2x80x94COxe2x80x94Z2xe2x80x94, xe2x80x94NHxe2x80x94NHxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94Oxe2x80x94Z2xe2x80x94, xe2x80x94NR3xe2x80x94SO2xe2x80x94NR3xe2x80x94Z2, xe2x80x94Oxe2x80x94Z2xe2x80x94Qxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Z2xe2x80x94Q or xe2x80x94Sxe2x80x94Z2xe2x80x94Qxe2x80x94 radicals,
in which Q represents a single bond, Oxe2x80x94Z3, R3Nxe2x80x94Z3 or Sxe2x80x94Z3;
Z1, Z2 and Z3 independently represent a single bond or a linear or branched alkylene radical having 1 to 6 carbon atoms,
and R6 represents a hydrogen atom or the OH group.
A subject of the present invention is new derivatives of amidines, their preparation and their therapeutic use.
The compounds of the invention correspond to general formula (I) characterized in that it comprises the compounds of general formula (Ixe2x80x2): 
in which
A represents:
either a 
xe2x80x83radical in which R1, R2 and R3 represent, independently, a halogen, the OH or SR6 group or a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or a NR7R8 radical,
R4 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R5 represents a hydrogen atom, the OH or SR6 group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R6 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R7 and R8 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R9 radical in which R9 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which R10, R11 and R12 represent, independently, a hydrogen atom, the OH or SR6 group, a halogen or a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or a NR15R16 radical,
R13 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R14 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R15 and R16 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R17 radical in which R17 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which R18, R19 and R20 represent, independently, a hydrogen atom, a halogen, the OH or SR23 group, a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or an NR24R25 radical,
R21 and R22 independently represent a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
or R21 and R22 form together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including the already present nitrogen atom, the additional heteroatoms being independently chosen from the group constituted by the O, N and S atoms,
or furthermore R21 represents an alkylsulphonyl, alkylsulphoxide or alkylcarbonyl radical and then R22 represents H,
R23 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R24 and R25 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R9 radical in which R9 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R27 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms
or a 
xe2x80x83radical in which R28 and R29 represent, independently, a hydrogen atom or an OH group,
or a 
xe2x80x83radical in which R30 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R31 represents a linear or branched alkyl radical having 1 to 6 carbon atoms, or an arylalkyl, diarylalkyl, bis-arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, or also R31 represents a (heterocyclo)alkyl radical in which the heterocycle is saturated or unsaturated, has 3 to 7 members and includes at least a nitrogen atom, said nitrogen atom being optionally substituted by a hydrogen atom or an alkyl radical,
or a 
xe2x80x83radical in which R32 and R33 represent, independently, a hydrogen atom or an OH group,
or finally one of the 
xe2x80x83radicals,
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
or also B represents an NR34R35 radical, in which R34 and R35 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or R34 and R35 form together with the nitrogen atom a non aromatic heterocycle with five to six members, the elements of the chain being chosen from a group comprising xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
X represents a bond or a xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94CO, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94NR36xe2x80x94, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94COxe2x80x94, (CH2)mxe2x80x94C(OH)(CH3)xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90Nxe2x80x94 radical;
Y represents a bond or a xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94 radical,
Q representing a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, piperidine, 1,2,3,6-tetrahydropyridine, pyrrolidine, azetidine or thiazolidine radical or a saturated carbon ring having 3 to 7 members;
"PHgr" represents a bond or a xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94Sxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94COxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94 or xe2x80x94COxe2x80x94(CH2)pxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94 radical;
R36 and R37 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R38 radical in which R38 represents a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
R39 represents a hydrogen atom or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
m, n, p, q, r and s being integers from 0 to 6;
it being understood that:
if A represents the 
radical then Y represents the piperidine radical;
if A represents the 
radical then Y represents a xe2x80x94(CH2)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94 radical in which Q represents a saturated carbon ring having 3 to 7 members;
said general formula (I) also comprising the following compounds:
2-hydroxy-5-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,5-dihydroxy-N-{2-[4[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
2-hydroxy-3-isopropyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,6-dihydroxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-4,6-dimethoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-3,5-di-tert-butyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
2-hydroxy-3,5-diisopropyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-4-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-3-isopropyl-5-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
N-(2-hydroxy-3-tert-butyl-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-butanamide;
N-(3-hydroxy-4-methoxyphenyl)-2-thiophenecarboximidamide;
N-(3-hydroxy-4-methylphenyl)-2-thiophenecarboximidamide;
N-(4-methoxyphenyl)-2-thiophenecarboximidamide;
N-(3,5-dimethyl-4-hydroxyphenyl)-2-thiophenecarboximidamide;
N-(3,5-dichloro-4-hydroxyphenyl)-2-thiophenecarboximidamide;
N-(2,6-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-2-thiophenecarboximidamide;
N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
1-(2-hydroxy-4,6-dimethoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;
N-(2-hydroxy-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-butanamide;
N-(2-hydroxy-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-propanamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-hydroxy-5-methoxy-3-methylbenzamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(2-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(3,4-dihydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide;
Nxe2x80x2-(4-{2-[(2-hydroxy-4,6-dimethoxybenzyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
or also the salts of the products of general formula (I).
By alkyl, when no more precision is given, is understood a linear or branched alkyl radical having 1 to 6 carbon atoms. By cycloalkyl, when no more precision is given, is understood a carbonated monocyclic system having 3 to 7 carbon atoms. By alkenyl, when no more precision is given, is understood a linear or branched alkyl radical having 1 to 6 carbon atoms and presenting at least one unsaturation (double bond). By alkynyl, when no more precision is given, is understood a linear or branched alkyl radical having 1 to 6 carbon atoms and presenting at least one double unsaturation (triple bond). By carbocyclic or heterocyclic aryl is understood a carbocyclic or heterocyclic system comprising at least an aromatic ring, a system being said heterocyclic when at least one of the cycles that constitute it comprises a heteroatom (O, N or S). By heterocycle is understood a mono- or polycyclic system, said system comprising at least a heteroatom chosen from O, N and S and being saturated, partially or totally unsaturated or aromatic. By haloalkyl is understood an alkyl radical of which at least one of the hydrogen atoms (and optionally all of them) is replaced by a halogen atom.
By alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl and aralkyl radicals is understood respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl and (heterocyclo)alkyl of which the alkyl radical has the meaning indicated previously.
By heterocycle is notably understood the thiophene, piperidine, piperazine, quinoline, indoline and indole radicals. By linear or branched alkyl having 1 to 6 carbon atoms, is understood in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. Finally, by halogen, is understood fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds of general formula (Ixe2x80x2) are such that:
A represents:
either a 
By heterocycle is in particular understood the thiophene, piperidine, piperazine, quinoline, indoline and indole radicals. By linear or branched alkyl having 1 to 6 carbon atoms, is understood in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. Finally, by halogen, is understood fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds of general formula (Ixe2x80x2) are such that:
A represents:
either a 
xe2x80x83radical in which R1, R2 and R3 represent, independently, the OH or SR6 group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R4 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R5 represents a hydrogen atom, the OH or SR6 group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R6 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which R18, R19 and R20 represent, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R21 and R22 represent independently a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
or R21 and R22 form together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including the already present nitrogen atom, the additional heteroatoms being independently chosen from the group constituted by the O, N and S atoms,
or also R21 represents an alkylsulphonyl or alkylcarbonyl radical and then R22 represents H,
or a 
xe2x80x83radical in which R10, R11 and R12 represent, independently, a hydrogen atom, the OH or SR14 group, a halogen or linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms,
R13 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R14 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R527 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms
or a 
xe2x80x83radical in which R28 and R29 represent, independently, a hydrogen atom or an OH group,
or a 
xe2x80x83radical in which R30 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R31 represents a linear or branched alkyl radical having 1 to 6 carbon atoms, or an arylalkyl, diarylalkyl, bis-arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, or R31 further represents a (heterocyclo)alkyl radical in which the heterocycle is saturated or unsaturated, has 3 to 7 members and includes at least a nitrogen atom, said nitrogen atom being optionally substituted by a hydrogen atom or an alkyl radical,
or a 
xe2x80x83radical in which R32 and R33 represent, independently, a hydrogen atom or an OH group,
or finally one of the 
xe2x80x83radicals
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
X represents a bond or a xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94CO, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94NR36xe2x80x94, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94COxe2x80x94 or xe2x80x94(CH2)mxe2x80x94C(OH)(CH3)xe2x80x94COxe2x80x94 radical;
Y represents a bond or a xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94 radical,
Q representing a piperazine, piperidine, 1,2,3,6-tetrahydropyridine, azetidine or thiazolidine radical or a saturated carbon ring having 3 to 7 members;
"PHgr" represents a bond or a xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94 radical;
R36 and R37 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R38 radical in which R38 represents a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
R39 represents a hydrogen atom or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
m, n, p, q, r and s being integers from 0 to 6.
Among the A radicals which can be used for the invention, the radicals of the type 
in which R31 represents a linear or branched alkyl radical having 1 to 6 carbon atoms, an aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, diarylalkyl or bis-arylalkyl radical, and notably those in which R17 represents the methyl, benzyl or naphthylmethyl radical will be preferably preferred.
Preferably, the compounds according to the invention are one of the following compounds:
2-hydroxy-5-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-5-methylthio-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,5-dihydroxy-N-{2-[4[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
2-hydroxy-3-isopropyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,6-dihydroxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-4,6-dimethoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-4,5,6-trimethoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2-hydroxy-3,5-di-tert-butyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
2-hydroxy-3,5-diisopropyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,4-dihydroxy-3,6-dimethyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
tert-butyl 2-{[(4-{[amino(2-thienyl)methylidene]amino}phenethyl)amino]-carbonyl}-4-methoxyphenylcarbamate;
2-amino-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-5-methoxybenzamide;
5-amino-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-hydroxybenzamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-hydroxy-5-methoxy-3-methylbenzamide;
N-[2-(4-{[amino(2-thienyl)methylidene]amino}anilino)-2-oxoethyl]-3,5-di(tert-butyl)-4-hydroxybenzamide;
Nxe2x80x2-{4-[4-(1,2,3,4-tetrahydro-2-naphthalenylcarbonyl)-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-{4-[(methylsulphonyl)amino]phenyl}butanamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(dimethylamino)phenyl]butanamide;
5-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(dimethylamino)phenyl]pentanamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(2-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(3,4-dihydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenamide;
(4R)-2-(3-{[amino(2-thienyl)methylidene]amino}-phenyl)-N-[4-(dimethylamino)phenyl]-1,3-thiazolidine-4-carboxamide;
Nxe2x80x2-[4-(4-{2-[3,5-di(tert-butyl)-4-hydroxy-phenoxy]acetyl}-1-piperazinyl)phenyl]-2-thiophenecarboximidamide;
N-{4-[4-(2-{[3,5-di(tert-butyl)-4-hydroxyphenyl]thio}acetyl)-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{4-[2-(4-hydroxy-2,3,5,6-tetramethylphenoxy)-acetyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
N-(4-{[amino(2-thienyl)methylidene]amino}-phenethyl)-2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]acetamide;
N-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-ethyl}amino)ethyl]phenyl}-2-thiophenecarboximidamide;
tert-butyl 3-{[amino(2-thienyl)methylidene]amino}benzyl{3-[4-(dimethylamino)anilino]-3-oxopropyl}carbamate;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylamino)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(4-methyl-1-piperazinyl)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(4-morpholinyl)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-benzyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxybenzyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
N-(4-{[(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-amino]methyl}phenyl)acetamide;
Nxe2x80x2-[4-(2-{[(8-hydroxy-2-quinolinyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-phenyl-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxy-3-methoxybenzyl]amino}-ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[(2-hydroxy-4,6-dimethoxybenzyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl](methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
4-{[(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-amino]methyl}-1-pyridiniumolate;
Nxe2x80x2-[4-(2-{[(2-hydroxy-4,6-dimethoxyphenyl)methylidene]-amino}ethyl)phenyl]-2-thiophenecarboximidamide;
tert-butyl 4-{[amino(2-thienyl)methylidene]amino}phenethyl(2-hydroxy-4,6-dimethoxybenzyl)carbamate;
Nxe2x80x2-{4-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]phenyl}-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-{4-[(1-benzhydryl-3-azetidinyl)oxy]phenyl}-2-thiophene-carboximidamide;
Nxe2x80x2-[4-(2-quinolinylmethoxy)phenyl]-2-thiophene-carboximidamide;
Nxe2x80x2-(4-{4-[2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)butanoyl]-1-piperazinyl}phenyl)-2-thiophene-carboximidamide;
N-{4-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)ethyl]phenyl}-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{4-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-{4-[2-({[4-(dimethylamino)anilino]carbonyl}amino)-ethyl]phenyl}-2-thiophenecarboximidamide;
N-{[1-(4-{[amino(2-thienyl)methylidene]-amino}phenyl)-cyclobutyl]methyl}-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamide;
Nxe2x80x2-{4-[4-(5-methoxy-1H-indol-3-yl)-1-piperidinyl]-phenyl}-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[5-(dimethylamino)-2-hydroxy-3-methoxybenzyl]-(methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-{1-[3-(dimethylamino)propyl]-2,3-dihydro-1H-indol-5-yl}butanamide;
3-[(5-{[amino(2-thienyl)methylidene]amino}-2-methoxybenzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
or a salt of the latter.
More preferentially, the compounds according to the invention are one of the following compounds:
2-hydroxy-5-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,5-dihydroxy-N-{2-[4[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
2-hydroxy-4,6-dimethoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
N-(2-hydroxy-3-tert-butyl-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-butanamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-2H-1-benzopyran-2-carboxamide;
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{1-[4-[(2-thienyl(imino)methyl)amino]phenyl]methyl}-2H-1-benzopyran-2-carboxamide;
N-(2-hydroxy-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-propanamide;
5-amino-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-hydroxybenzamide;
5-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(dimethylamino)phenyl]pentanamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(2-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxyphenyl)-2-propenamnide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(3,4-dihydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenamide;
N-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-ethyl}amino)ethyl]phenyl}-2-thiophenecarboximidamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylamino)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino-N-[4-(4-methyl-1-piperazinyl)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(4-morpholinyl)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-benzyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxybenzyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
N-(4-{[(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-amino]methyl}phenyl)acetamide;
Nxe2x80x2-[4-(2-{[(8-hydroxy-2-quinolinyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-phenyl-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl](methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-{4-[2-({[4-(dimethylamino)anilino]carbonyl}amino)-ethyl]phenyl}-2-thiophenecarboximidamide;
N-{[1-(4-{[amino(2-thienyl)methylidene]-amino}phenyl)-cyclobutyl]methyl}-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamide;
or the salts of the latter.
Also more preferentially, the compounds according to the invention are one of the following compounds:
2-hydroxy-5-methoxy-N-{2-[4-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;
2,5-dihydroxy-N-{2-[4[(2-thienyl(imino)methyl)amino]phenyl]ethyl-benzamide;
N-(2-hydroxy-5-methoxy)-4-{[2-thienyl](imino)methyl]amino}benzene-propanamide;
5-amino-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-hydroxybenzamide;
5-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(dimethylamino)phenyl]pentanamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(2-hydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(3,4-dihydroxyphenyl)-2-propenamide;
(E)-N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenamide;
N-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-ethyl}amino)ethyl]phenyl)}-2-thiophenecarboximidamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylamino)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-benzyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxybenzyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(8-hydroxy-2-quinolinyl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl](methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[4-phenyl-3,6-dihydro-1(2H)-pyridinyl]ethyl}phenyl)-2-thiophenecarboximidamide;
or the salts of the latter.
Finally, the following compounds will be also more particularly preferred:
N-(2-hydroxy-5-methoxy)-4-{[2-thienyl(imino)methyl]amino}benzene-propanamide;
N-{4-[2-({2-[3,5-di(tert-butyl)-4-hydroxyphenoxy]-ethyl}amino)ethyl]phenyl}-2-thiophenecarboximidamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[4-(dimethylamino)phenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-[3,5-di(tert-butyl)-4-hydroxyphenyl]propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-methyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(1-benzyl-2,3-dihydro-1H-indol-5-yl)propanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxybenzyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl](methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
or the salts of the latter.
In certain cases, the compounds according to the present invention can comprise asymmetrical carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. the xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
The invention furthermore offers, as new industrial products, the compounds of general formula (IS), which are useful synthesis intermediates in the preparation of products of general formula (I), 
general formula (IS) in which
A represents:
either a 
3-[(3-{[amino(2-thienyl)methylidene]amino}benzyl)amino]-N-[1-(1-naphthylmethyl)-2,3-dihydro-1H-indol-5-yl]propanamide;
Nxe2x80x2-[4-(2-{[5-(dimethylamino)-2-hydroxybenzyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3-methoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-[4-(2-{[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{2-[[(E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-2-propenyl](methyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
or the salts of the latter.
In certain cases, the compounds according to the present invention can comprise asymmetrical carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. the xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
The invention furthermore offers, as new industrial products, the compounds of general formula (IS), which are useful synthesis intermediates in the preparation of products of general formula (I), 
general formula (IS) in which
A represents:
either a 
xe2x80x83radical in which R1, R2 and R3 represent, independently, a halogen, the OH or SR6 group or a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or a NR7R8 radical,
R4 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R5 represents a hydrogen atom, the OH or SR6 group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
R6 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R7 and R8 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R9 radical in which R9 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which R10, R11 and R12 represent, independently, a hydrogen atom, the OH or SR14 group, a halogen or a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or a NR15R16 radical,
R13 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R14 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R15 and R16 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R17 radical in which R17 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which R18, R19 and R20 represent, independently, a hydrogen atom, a halogen, the OH or SR23 group, a linear or branched alkyl, alkenyl or alkoxy radical having 1 to 6 carbon atoms, or an NR24R25 radical,
R21 and R22 independently represent a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
or R21 and R22 form together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group constituted by the O, N and S atoms,
or also R21 represents an alkylsulphonyl, alkylsulphoxide or alkylcarbonyl radical and R22 represents H,
R23 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R24 and R25 independently representing a hydrogen atom, an OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R26 radical in which R26 represents a linear or branched alkyl radical having 1 to 6 carbon atoms;
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R5 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms
or a 
xe2x80x83radical in which R28 and R29 represent, independently, a hydrogen atom or an OH group,
or a 
xe2x80x83radical in which R30 represents a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms,
or a 
xe2x80x83radical in which T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2, and R31 represents a linear or branched alkyl radical having 1 to 6 carbon atoms, or an arylalkyl, diarylalkyl, bis-arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, or to R31 also represents an (heterocyclo)alkyl radical in which the heterocycle is saturated or unsaturated, has 3 to 7 members and includes at least one nitrogen atom, said nitrogen atom being optionally substituted by a hydrogen atom or an alkyl radical,
or a 
xe2x80x83radical in which R32 and R33 represent, independently, a hydrogen atom or an OH group,
or finally one of the 
xe2x80x83radicals,
B represents a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms,
or also B represents an NR34R35 radical, in which R34 and R35 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or R34 and R35 form together with the nitrogen atom a non aromatic heterocycle with five to six members, the elements of the chain being chosen from a group comprising xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
X represents a bond or a xe2x80x94(CH2)mxe2x80x94, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94NR36xe2x80x94, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94NR36xe2x80x94(CH2)mxe2x80x94COxe2x80x94, xe2x80x94(CH2)mxe2x80x94C(OH)(CH3)xe2x80x94COxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CHxe2x95x90Nxe2x80x94 radical;
Y represents a bond or a xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94 radical,
Q representing a piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, piperidine, 1,2,3,6-tetrahydropyridine, pyrrolidine, azetidine or thiazolidine radical or a saturated carbon ring having 3 to 7 members;
"PHgr" represents a bond or a xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94Sxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)pxe2x80x94COxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94 or xe2x80x94COxe2x80x94(CH2)pxe2x80x94NR37xe2x80x94(CH2)qxe2x80x94 radical;
R36 and R37 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R38 radical in which R38 represents a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
R39 represents a hydrogen atom or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
Z represents NO2 or NH2;
m, n, p, q, r and s being integers from 0 to 6;
it being understood that:
if A represents the 
xe2x80x83radical then Y represents the piperidine radical;
if A represents the 
xe2x80x83radical then Y represents a xe2x80x94(CH2)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94 radical in which Q represents a saturated carbon ring having 3 to 7 members;
The invention further relates to the compounds of general formula (ISxe2x80x2), which are synthesis intermediates in the preparation of products of general formula (I) in which A is an substituted indoline radical as defined previously, X represents the xe2x80x94NR15xe2x80x94COxe2x80x94 radical, Y represents a bond and "PHgr" represents a xe2x80x94(CH2)pxe2x80x94NR16xe2x80x94(CH2)qxe2x80x94 radical, 
general formula (ISxe2x80x2) in which
xcfx80 represents a hydrogen atom or a protective group of carbamate type;
R36 and R37 represent, independently, a hydrogen atom, a linear or branched alkyl radical having 1 to 6 carbon atoms or a xe2x80x94COxe2x80x94R38 radical in which R38 represents a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
T represents a xe2x80x94(CH2)kxe2x80x94 radical, k representing 1 or 2;
R31 represents a linear or branched alkyl radical having 1 to 6 carbon atoms, arylalkyl, diarylalkyl, bis-arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl, or R31 also represents a (heterocyclo)alkyl radical in which the heterocycle is saturated or unsaturated, has 3 to 7 members and includes at least one nitrogen atom, said nitrogen atom being optionally substituted by a hydrogen atom or an alkyl radical;
according to a method in the literature (Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
In the particular case where A represents a pyridine-oxide, the pyridine oxidation is only carried out during the last synthesis stage because of the fragility of these compounds in reducing medium. Metachloroperbenzoic acid, used as oxidizing agent, allows pyridine-oxide derivatives of general formula (Ixe2x80x2) to be obtained.
Salification of the compounds of general formula (Ixe2x80x2), when carried out in the presence of a strong acid such as, for example, hydrochloric acid, allows the amines which have been protected in the form of tert-butylcarbamate during the synthesis to be released simultaneously.
In the case where B is an amine, the final compounds of general formula (Ixe2x80x2) are guanidines. These can be prepared, for example, by condensation of the amines of general formula (II) with the derivatives of general formula (IV) or (IVxe2x80x2). The reagents of general formula (IV) in which L represents, for example, a pyrazole ring are condensed with the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502), similarly for the reagents of general formula (IVxe2x80x2) in which L represents, for example, a pyrazole ring and Gp represents the tBuOCO group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp represents the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During the final stage of the synthesis, deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.
Therefore, a subject of the invention is also a process for the preparation of compounds of general formula (Ixe2x80x2) as defined above, said process being characterized in that a compound of general formula (II) 
in which A, B. X, Y, "PHgr" and R39 are as defined above,
In accordance with the invention, the compounds of general formula (I) can be prepared by the process described below.
The compounds of the invention corresponding to general formula (I) but not to the general formula (Ixe2x80x2) can be prepared according to the procedures described in the examples. The products of general formula (Ixe2x80x2) are prepared as described hereafter.
The compounds of general formula (Ixe2x80x2) can be prepared from intermediates of general formula (II) according to Diagram 1 where A, B, X, Y, "PHgr" and R12 are as defined above and Gp is a protective group of carbamate type, for example the t-butoxycarbonyl group. 
The aniline derivatives of general formula (II) can be condensed with compounds of general formula (III), in which L represents a parting group (for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical), in order to produce the final compounds of general formula (Ixe2x80x2) of substituted amidine type (cf. Diagram 1). For example, for B=thiophene, the derivatives of general formula (II) can be condensed with of S-methylthiophene thiocarboxamide hydroiodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). Condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably comprised between 50 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
In the particular case where A represents a pyridine-oxide, the pyridine oxidation is only carried out during the last synthesis stage because of the fragility of these compounds in reducing medium. Metachloroperbenzoic acid, used as oxidizing agent, allows pyridine-oxide derivatives of general formula (Ixe2x80x2) to be obtained.
Salification of the compounds of general formula (Ixe2x80x2), when carried out in the presence of a strong acid such as, for example, hydrochloric acid, allows the amines which have been protected in the form of tert-butylcarbamate during the synthesis to be released simultaneously.
In the case where B is an amine, the final compounds of general formula (Ixe2x80x2) are guanidines. These can be prepared, for example, by condensation of the amines of general formula (II) with the derivatives of general formula (IV) or (IVxe2x80x2). The reagents of general formula (IV) in which L represents, for example, a pyrazole ring are condensed with the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502), similarly for the reagents of general formula (IVxe2x80x2) in which L represents, for example, a pyrazole ring and Gp represents the tBuOCO group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp represents the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During the final stage of the synthesis, deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.
Therefore, a subject of the invention is also a process for the preparation of compounds of general formula (Ixe2x80x2) as defined above, said process being characterized in that a compound of general formula (II) 
in which A, B, X, Y, "PHgr" and R39 are as defined above,
is reacted with the intermediate of general formula (III) 
xe2x80x83in which B is as defined above and L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical.
Therefore, a subject of the invention is also a process for the preparation of compounds of general formula (Ixe2x80x2) as defined above and in which B represents an amine, said process being characterized in that a compound of general formula (II) 
xe2x80x83in which A, B, X, Y, "PHgr" and R39 are as defined above, is reacted
a) either with the intermediate of general formula (IV) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical,
b) or with the intermediate of general formula (IVxe2x80x2) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical, and Gp is a protective group of carbamate type, for example the t-butoxycarbonyl group,
xe2x80x83this reaction being followed, in the case where the reaction with the compound of general formula (IVxe2x80x2) is chosen, by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid.
The compounds of general formula (Ixe2x80x2) in which A represents a 2,3,5-trimethyl-benzoquinone and X=xe2x80x94(CH2)mxe2x80x94C(OH)(CH3)xe2x80x94COxe2x80x94 with B, Y, "PHgr" and R39 as defined above can be obtained from the compounds comprising a Trolox group, Diagram 1xe2x80x2. The reactivity of the Trolox with respect to the free radicals allows a chemical modification of this group to be envisaged, in fact, the action of FeCl3 in an aqueous medium (Helv. Chim. Acta (1963) 46, 333) causes a radicular opening of the benzopyranic system and leads to the compounds of general formula (Ixe2x80x2). 
The non-commercial intermediates of general formula (II), are obtained either by detachment of a protective group, or by reduction of a precursor of nitro type, as illustrated in the synthesis diagrams below.
Reduction of the Precursors of Nitro Type:
The reduction of the nitro function of the intermediates of general formula (V), Diagram 2, in which A, X, Y, "PHgr" and R39 are as defined above, is generally carried out by catalytic hydrogenation, in ethanol, in the presence of Pd/C, except in the case of molecules sensitive to these conditions where the nitro group is selectively reduced, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) or using NaBH4xe2x80x94BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or then by using Raney Ni with hydrazine hydrate added (Monatshefte fxc3xcr Chemie, (1995), 126, 725-732), or also using SnCl2 in the presence of Zn (Synthesis (1996), (9), 1076-1078). 
In the particular case of the indolic derivatives of general formula (V) (Diagram 6), the gentle reduction conditions of the nitro function (Zn in acetic acid) are inevitably accompanied by the loss of the unsaturation at the level of 1,2,3,6-tetrahydropyridine in order to produce the piperidine.
Deprotection of the Amino Group:
The intermediates of general formula (II), in which A, X, Y, "PHgr" and R39 are as defined above, can also be prepared from the intermediates of general formula (VI), Diagram 3, which are compounds comprising an amine protected in the form, for example, of 2,5-dimethylpyrrole (N=Gpxe2x80x2) or of tert-butyl carbamate (NH-Gp). The pyrroles, for example, are deprotected by heating in the presence of hydroxylamine hydrochloride for at least 24 hours in order to finally produce the primary amines of general formula (II). The amines protected in the form of tert-butyl carbamates are released in a standard fashion in acidic medium by treatment with trifluoroacetic or hydrochloric acid. 
Synthesis of the Carboxamides:
The carboxamides of general formula (V), Diagram 4, in which X represents xe2x80x94COxe2x80x94NR36xe2x80x94 and A, Y, Q, "PHgr", R39 and R36 are as defined above, are prepared by condensation of the acids of general formula (VII) with the commercial arnines of general formula (VIII) under standard conditions for peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)).
The syntheses of the non-commercial acids of general formula (VII) are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. 
(Axe2x80x94Xxe2x80x94COxe2x80x94N series)
The carboxamides of general formula (V), Diagram 5, in which X represents xe2x80x94Oxe2x80x94(CH2)mxe2x80x94, xe2x80x94Sxe2x80x94(CH2)mxe2x80x94 or xe2x80x94NR15xe2x80x94(CH2)mxe2x80x94 with A, Y, "PHgr", R39 and R36 as defined above (Q being a heterocycle), are prepared by condensation of the acids of general formula (IX) with the amines of general formula (X) or (XXII) under standard conditions for peptide synthesis as described previously. The syntheses of the acids of general formula (IX) and of the amines of general formula (X), non-commercial, are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. 
Synthesis of the Derivatives of 1,2,3,6-Tetrahydropyridine:
The indolic derivatives of general formula (Vxe2x80x2), in which Q represents 1,2,3,6-tetrahydropyridine, "PHgr", R9 and R12 being as defined above, are prepared from the substituted commercial indoles of general formula (XI), Diagram 6. The experimental protocol of the condensation reaction with the piperidone is described in Eur. J. Med. Chem. (1987) 22, 33-43. The intermediate of general formula (XII) is then condensed in a standard fashion with the halogenated derivatives of general formula (XIII) in the presence of a base such as, for example, Na2CO3, in an appropriate polar solvent such as for example DMF, in order to produce the intermediates of general formula (Vxe2x80x2) (specific case of the intermediates of general formula (V)). 
The derivatives of general formula (Va) (specific case of the intermediates of general formula (V)), Diagram 7, in which Q represents 1,2,3,6-tetrahydropyridine, "PHgr", Y and R39 being as defined above, Hal being a halogen atom, are also prepared by condensation of 4-phenyl-1,2,3,6-tetrahydropyrine with the halogenated derivatives of general formula (XIII) in the presence of a base such as, for example, K2CO3, in an appropriate polar solvent such as, for example, DMF. Alternatively, the compounds of general formula (Va) are accessible by Mitsonobu type condensation (Synthesis (1981), 1) between 4-phenyl-1,2,3,6-tetrahydropyrine and alcoholic derivatives of general formula (XVIII). 
Synthesis of Theophylline Derivatives:
The theophylline derivatives of general formula (Vb) (specific case of the intermediates of general formula (V)), Diagram 8, in which Y, "PHgr" and R39 are as defined above, are prepared by condensation of commercial Theophylline with the halogenated derivatives of general formula (XIV) in the presence of a base such as, for example, NaOH, in a hydro-alcoholic solvent. 
Synthesis of the Ethers of General Formula (V):
When "PHgr" represents xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94, with A, Q, R39, p and q as defined above, the ethers of general formula (V), Diagram 9, can be prepared in a single stage by condensation of the alcohols of general formula (XV) with the halogenated derivatives of general formula (XVI) in the presence of a base such as for example NaH in a polar solvent such as for example THF. 
When "PHgr" represents xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94, with A, R39, p and q as defined above, the ethers of general formula (V) can also be prepared from the halogenated derivatives of formula (XVII) and the alcohols of general formula (XVIII), Diagram 10, in the presence of a base such as for example NaH in a polar solvent such as for example DMF. 
Synthesis of Carboxamides (Axe2x80x94Xxe2x80x94Nxe2x80x94COxe2x80x94 series):
The carboxamides of general formula (V), Diagram 11, in which A, R39, R36, Y and "PHgr" are as defined above, are prepared under the same peptidic coupling conditions as the carboxamides of the Axe2x80x94Xxe2x80x94COxe2x80x94Nxe2x80x94 series. The preparations of the non-commercial amines of general formula (XIX) and acids of general formula (XX) are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. 
Synthesis of the Amines by Reducing Amination
The amines of general formula (V), Diagram 12, in which A, R39, R36, Y, m and "PHgr" are as defined above, can be prepared by condensation of an aldehyde of general formula (XXI) with a commercial amine of general formula (XXII) in a reducing medium. The reaction takes place in an alcoholic solvent such as, for example, methanol in the presence of a pulverulent 4 xc3x85 molecular sieve, activated beforehand, and of a reducing agent such as, for example, NaBH4 or NaBH3CN. Before the addition of the reducing agent, some imines can be isolated as intermediates of general formula (V).
The secondary amines of general formula (V) are then protected in the form of tert-butyl carbamate in the presence of di-tert-butyldicarbonate, and of a base such as, for example, triethylamine and in a solvent such as, for example, dichloromethane. The syntheses of the non-commercial aldehydes of general formula (XXI) are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. 
The amines of general formula (V), Diagram 13, in which A, X, R39, R37, p and q are as defined above, can also be prepared by condensation of an amine of general formula (XXIII) with a commercial aldehyde of general formula (XXIV) in a reducing medium under the conditions described previously. The secondary amines of general formula (V) are then protected in the form of tert-butyl carbamate, under the conditions described previously. The syntheses of the amines of general formula (XXIII) are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. Moreover, the non-commercial aldehydes of general formula (XXVI) can be prepared according to J. Org. Chem., 1993, 58, 1385-92. 
Synthesis of the Amines by Reduction of the Carboxamides:
The amines of general formula (V), Diagram 14, in which A, X, R39, R37 and q are as defined above, are accessible by reduction of the carboxamide derivatives of general formula (V), the synthesis of which is described in the xe2x80x9cSynthesis of the carboxamidesxe2x80x9d chapter (Diagram 4). The reduction stage is carried out in an anhydrous medium, by heating at 70-80xc2x0 C., in the presence of a carboxamide selective reagent such as, for example, BH3.THF, in a solvent such as, for example, THF. The secondary amines thus prepared can be protected in the form of tert-butyl carbamate under the conditions described previously 
Synthesis of the Ureas:
The ureas of general formula (V), Diagram 15, in which A, Y, "PHgr", R39, R36 and R37 are as defined above, are accessible by reaction of the amines of general formula (XIX) with the amines of general formula (XXII) in the presence of triphosgene and of a base such as, for example, diisopropylethylamine in an inert solvent such as dichloromethane according to an experimental protocol described in J. Org. Chem. (1994) 59 (7), 1937-1938. 
Synthesis of Pyrrolidinyl-pyrimidine Derivatives:
The pyrimidine derivatives of general formula (V), Diagram 16, in which Q represents piperazine, "PHgr" and R39 being as defined above, are prepared by condensation of 4-chloro-2,6-di-pyrrolidin-1-yl-pyrimidine (J. Med. Chem. (1990) 33 (4), 1145-1151) with the piperazine derivatives of general formula (X), by heating, for 24 to 48 hours, in anhydrous pyridine at a temperature of 80-110xc2x0 C. 
Synthesis of the Carboxamides (Axe2x80x94Xxe2x80x94COxe2x80x94N series):
The carboxamides of general formula (VI), Diagram 17, in which A, Y, "PHgr", R39, R36, Gp and Gpxe2x80x2 are as defined above, can be prepared from the commercial acids of general formula (VII) and the amines of general formulae (XXV) or (XXVI) under the standard conditions for peptide synthesis as described previously. The syntheses of the amines of general formulae (XXV) and (XXVI) are described in the xe2x80x9cPreparation of the Intermediatesxe2x80x9d chapter. 
Synthesis of the Carboxamides (Axe2x80x94Xxe2x80x94Nxe2x80x94CO series):
The carboxamides of general formula (VI), Diagram 18, in which A, Y, "PHgr", R39, R36 and Gp are as defined above, can be prepared by condensation of the amines of general formula (XIX), described previously, with the acids of general formula (XXVII) under the standard conditions for peptide synthesis as described previously. The acids of general formula (XXVII) are easily accessible by protection of the aniline function in the form, for example, of a tert-butyl carbamate under standard conditions. 
Synthesis of Intermediates (VII):
The non-commercial acids of general formula (VII) in which A is as defined above are accessible using the methods of the literature. For example, 2-hydroxy-4,5,6-trimethoxybenzoic acid is obtained in two stages from 3,4,5-trimethoxyphenol according to J. Org. Chem. (1961) 26, 1221-1223, Acta Chem. Scandinavica (1973) 27, 888-890 or Can. J Chem. (1972) 50, 1276-1282.
Certain acids of general formula (VII), in which A is as defined above, include an amine (R1 substituent) which has to be protected in the form of a carbamate, in particular teri-butyl, before carrying out the condensation stage. This protection is carried out under standard conditions described in xe2x80x9cM. Bodanszky et A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer Verlag, 1984)xe2x80x9d.
The acid derivatives of the benzofuranes are prepared using an experimental protocol described in J. Org. Chem. (1989) 54, 560-569.
Synthesis of Intermediates (IX):
The non-commercial acids of general formula (IX) in which X represents xe2x80x94Oxe2x80x94(CH2)mxe2x80x94 with A as defined above are prepared from the hydroquinones of general formula (IX.1) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). Condensation with commercial halogenoesters of general formula (IX.2) is carried out in the presence of a base such as, for example, K2CO3, by heating in a polar solvent such as, for example, THF for at least 5 hours. The esters of general formula (IX.3) obtained intermediately are then deprotected (in an acid medium in the case of the tert-butyl esters) in order to produce the acids of general formula (IX). 
The acids of general formula (IX) in which X represents xe2x80x94Sxe2x80x94(CH2)mxe2x80x94 with A as defined above, are prepared according to the literature (J. Med. Chem. (1997) 40 (12), 1906-1918).
Synthesis of Intermediates (X):
The non-commercial amines of general formula (X), in which Q represents homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, are synthesized in three stages from the corresponding commercial diamines. The diamines are selectively monoprotected in the form of carbamate (Synthesis (1984), (12), 1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reaction by nucleophilic substitution on a halogen nitrobenzene, in particular 4-fluoronitrobenzene. The amines, previously protected, are released in the last stage, according to methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce the intermediates of general formula (X).
Synthesis of Intermediates (XIX):
The amines of general formula (XIX), which are indoline or 1,2,3,4-tetrahydroquinoline derivatives, Diagram 11.1, in which T and R31 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (XIX.1). 6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J Chem. (1952), 30, 720-722. The alkylation of the amine is carried out in a standard fashion by a strong base such as, for example, NaH, in an aprotic polar solvent such as, for example, DMF in the presence of a halogenated derivative such as, for example, Mel or PhCH2Br. The nitro derivative of general formula (XIX.2) obtained intermediately is then reduced, for example, by Raney Nickel in the presence of hydrazine hydrate in order to produce the anilines of general formula (XIX). 
Certain non-commercial phenylenediamine derivatives of general formula (XIX) can also be prepared according to Farmaco (1951) 6, 713-717.
In the specific case where A is a phenolic derivative, the anilines of general formula (XIX) are obtained by hydrogenation, in the presence of Pd/C, of the nitrophenol precursor derivatives. The nitrated derivatives of the di-tert-butyl phenols are accessible according to a method described in J. Org. Chem. (1968) 33 (1), 223-226.
Synthesis of Intermediates (XX):
The non-commercial carboxylic acids of general formula (XX) in which R39, Y and "PHgr" are as defined above are accessible by methods described in literature. The syntheses of several xcfx89-(4xe2x80x2-nitrophenyl)alkanoic acids are described in J. Med. Chem. (1978) 21 (5), 430-437.
The synthesis of the carboxylic acids of general formula (XX), in which R1 and Y are as defined above and "PHgr"=thiazolidine, is carried out following a protocol described in Liebigs Ann. Chem. (1987), 927-934.
Synthesis of Intermediates (XXI):
The non-commercial aldehydes of general formula (XXI) in which A and m are as defined above are accessible from methods in the literature: Bull. Chem. Soc. Jpn. (1978) 51 (8), 2433-2434, Bioorg. Med. Chem. Lett. (1998) 8, 3453-3458.
Synthesis of Intermediates (XXIII):
The amines of general formula (XXIII), Diagram 13.1, in which A, X, R37, Gp and p are as defined above, are prepared by condensation of the amines of general formula (XIX), described previously, and the protected amino acids of general formula (XXIII.1), under the standard conditions of peptide synthesis (see chapter Synthesis of the carboxamides (Diagram 4)). Deprotection of the amine of compounds of general formula (XXIII.2) is then carried out in acidic medium such as, for example, trifluoroacetic acid or hydrochloric acid. 
Synthesis of Intermediates (XXV):
The amines of general formula (XXV), in which Y and "PHgr" are as defined above, are prepared in several steps from commercial aniline derivatives of general formula (XXV.1), Diagram 17.1. In order to protect the aniline function, a protective group is used which is resistant to a strong basic medium, for example the 2,5-dimethylpyrrole group. By the heating under reflux, in an appropriate solvent (e.g. toluene), of a mixture of the intermediate of general formula (XXV.1) with 2,5-hexanedione and paratoluenesulphonic acid, with simultaneous elimination of the water formed during the reaction, the intermediate of general formula (XXV.2) is obtained. The intermediate of general formula (XXV.3) is obtained by double alkylation of a carbon using two equivalents of a strong base, such as, for example, NaH in DMSO (J. Org. Chem. (1971) 36 (9), 1308-1309), in the presence of a dihalogenated derivative. The amines of general formula (XXV) are then obtained by reduction of the nitrile using, for example, LiAIH4, in a solvent such as, for example, anhydrous THF. 
Synthesis of Intermediates (XXVI):
The amines of general formula (XXVI), Diagram 17.2, in which R39 and "PHgr" are as defined above, are prepared in several stages from a commercial azetidine derivative and a halogenated derivative of general formula (XIII). The condensation stage is carried out in a standard fashion in the presence of a strong base such as, for example, NaH in an inert anhydrous solvent such as, for example, THF. Reduction of the nitro derivative by tin chloride (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842) produces the aniline derivative of general formula (XXVI.2) which is directly protected in the form of a tert-butyl carbamate under the conditions described previously. The amine of general formula (XXVI) is obtained by hydrogenolysis of the dibenzyl group in the presence of palladium hydroxide. 
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which this invention belongs. Similarly, all the publications, patent applications, all the patents and all other references mentioned here are incorporated by way of reference.